Manganese (Mn) is a neurotoxicant that is present in soil, air, and water. Investigations of occupationally- exposed groups, such as welders, provide an ideal opportunity to characterize dose-related dopaminergic system damage associated with Mn. Recent studies from our collaborating institutions demonstrate a high prevalence of Parkinsonism in workers with chronic exposure to Mn containing welding fumes and dopaminergic dysfunction on [18F] fluorodopa (FDOPA) PET. This study utilizes an established, well characterized cohort of welders with detailed exposure and clinical assessments, developed through NIEHS funded research projects. For this proposal, a cohort of 40 career welders with baseline FDOPA PET scans will undergo repeat PET imaging of the nigrostriatal dopamine system using FDOPA and first time imaging with the presynaptic dopaminergic radioligand [11C]dihydrotetrabenazine (DTBZ) and the post-synaptic dopamine D2 receptor selective radioligand [11C]N-methylbenperidol (NMB). These workers will be compared to a second group of non-welder reference subjects who will be imaged at baseline and four years. The specific goals of this project are: 1) to investigate progression of dopaminergic dysfunction in welding exposed workers as evidence of progressive neurotoxicity, 2) to use the radioligand DTBZ to investigate the dose-response relationship with welding fume exposure as an indicator of the underlying etiologic relationship between Mn and damage to the presynaptic dopaminergic system, and 3) to use the radioligand NMB to investigate the dose-response relationship with welding fume exposure as an indicator of the underlying etiologic relationship between Mn and damage to the postsynaptic dopamine system. This proposal uses state-of-the-art imaging methods to investigate the health effects of a common environmental and occupational health hazard. The results of this study will have broad implications for public and worker health worldwide and will inform future community based studies of metal neurotoxicity. In addition, this study, in conjunction with our previously published data, will provide converging evidence of the role of Mn as a nigrostriatal neurotoxin. The methods described in this application represent cutting edge molecular and MRI techniques and the institutions and investigators are ideally suited for this unique epidemiology and imaging proposal.